This is an application for a K01 award for Dr. Karmella Haynes, an assistant professor in the Ira A. Fulton School of Biological and Health Systems Engineering (SBHSE) at Arizona State University (ASU). Dr. Haynes is establishing herself as a young investigator in. This K01 award will provide Dr. Haynes with the protected time and support necessary to accomplish the following goals: (1) to become an expert in computational biology methods, (2) to become engaged in translational research collaborations with clinical scientists at the Mayo Clinic in Phoenix, AZ and Rochester, MN, and (3) to develop an independent research career. To achieve these goals, Dr. Haynes has assembled a mentoring team comprised of a principal mentor, Dr. Mark Spano, Research Professor in the SBHSE who is an expert in experimental nonlinear dynamics and complexity theory as applied to biological systems, and two co- mentors: Dr. Joshua LaBaer, a Professor and the Director of the Virginia G. Piper Center for Personalized Medicine (CPD) at the Biodesign Institute at ASU; and Dr. Pamela Silver, a Professor in the Department of Systems Biology and founding core faculty member at the Wyss Institute of Biologically Inspired Design at Harvard Medical School. The misregulation of chromatin, the central DNA-protein structures that package genetic material within human cells, is a well-recognized factor of oncogenesis and poor prognostic outcome. Dr. Haynes' research will focus on using a model system to develop and test synthetic chromatin proteins that interfere with the methyl-histone cancer-associated epigenetic signature (Aim 1), solving the problem of regulating cell-to-cell heterogeneity in the expression of chromatin-regulated genes (Aim 2), and reactivating chromatin-repressed tumor-suppressor genes with synthetic chromatin proteins (Aim 3). In Aim 1, Dr. Haynes will expand upon her research background in chromatin and synthetic biology to construct and quantitatively assess the activity of the synthetic proteins. In Aim 2, Dr. Haynes will work closely with Dr. Spano to computationally model and verify threshold protein concentrations at which cell phenotypes become uniform across a large population. In Aim 3, Dr. Haynes will work with Dr. LaBaer to complete transcription-profiling experiments in synthetic protein- treated cancer cells. The experiments will generate preliminary data that will form the basis of a methodology to use modular peptide motifs to build synthetic chromatin proteins that activate dormant therapeutic genes in a predictable, reliable manner. A study that applies this methodology to halt cancer progression in vivo without undesired pleiotropic effects will be proposed in an R01 grant application before the end of the K award.